title: ClC-7 expression levels critically regulate bone turnover, but not gastric acid secretion.
abstract: Mutations in the 2Cl(-)/1H(+)-exchanger ClC-7 impair osteoclast function and cause different types of osteoclast-rich osteopetrosis. However, it is unknown to what extent ClC-7 function has to be reduced to become rate-limiting for bone resorption. In osteoclasts from osteopetrosis patients expression of the mutated ClC-7 protein did not correlate with disease severity and resorption impairment. Therefore, a series of transgenic mice expressing ClC-7 in osteoclasts at different levels was generated. Crossing of these mice with Clcn7(-/-) mutants rescued the osteopetrotic phenotype to variable degrees. One resulting double transgenic line mimicked human autosomal dominant osteopetrosis. The trabecular bone of these mice showed a reduction of osteoblast numbers, osteoid, and osteoblast marker gene expression indicative of reduced osteoblast function. In osteoclasts from these mutants ClC-7 expression levels were 20 to 30% of wildtype levels. These reduced levels not only impaired resorptive activity, but also increased numbers, size and nucleus numbers of osteoclasts differentiated in vitro. Although ClC-7 was expressed in the stomach and PTH levels were high in Clcn7(-/-) mutants loss of ClC-7 did not entail a relevant elevation of gastric pH. In conclusion, we show that in our model a reduction of ClC-7 function by approximately 70% is sufficient to increase bone mass, but does not necessarily enhance bone formation. ClC-7 does not appear to be crucially involved in gastric acid secretion, which explains the absence of an osteopetrorickets phenotype in CLCN7-related osteopetrosis.
authors.affiliation: Institute of Medical Genetics and Human Genetics, Charité-Universitaetsmedizin Berlin, Berlin, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Supanchart
authors.forename: L
authors.initials: L
authors.lastname: Wartosch
authors.forename: C
authors.initials: C
authors.lastname: Schlack
authors.forename: J
authors.initials: J
authors.lastname: Kühnisch
authors.forename: D
authors.initials: D
authors.lastname: Felsenberg
authors.forename: J C
authors.initials: JC
authors.lastname: Fuhrmann
authors.forename: M-C
authors.initials: MC
authors.lastname: de Vernejoul
authors.forename: T J
authors.initials: TJ
authors.lastname: Jentsch
authors.forename: U
authors.initials: U
authors.lastname: Kornak
mesh_terms: D000818:Animals; D016723:Bone Remodeling; D001862:Bone Resorption / Q000150:complications / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D002452:Cell Count; D002454:Cell Differentiation / Q000235:genetics; D002459:Cell Fusion; D018118:Chloride Channels / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D005744:Gastric Acid / Q000378:metabolism*; D005799:Genes, Dominant; D005808:Genes, Recessive; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051379:Mice; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology; D010012:Osteogenesis / Q000235:genetics; D010022:Osteopetrosis / Q000150:complications / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D010641:Phenotype
chemical_list: C097540:CLCN7 protein, human; D018118:Chloride Channels; C490803:Clcn7 protein, mouse; D002118:Calcium
keywords: Calcium homeostasis; Chloride channel; Osteoclast; Osteoclast–osteoblast coupling; Osteopetrosis; Proton secretion